DESCRIPTION: Human prostatic acid phosphatase (hPAP) is a major secretory protein of the prostate gland that is found at greater than 1 mg/mL concentrations in semen. hPAP was the first tumor marker protein identified in blood serum over 60 years ago. Since its discovery, hPAP has been extensively studied, and the applicant has recently determined its 3-D molecular structure to 3.1 A resolution. The focus of the proposed research stems from recent reports in the literature that hPAP inhibits natural killer (NK) cell activity by 85 percent as well as superoxide production by neutrophils by 50 percent. Additional reports correlate a decline in NK cell activity with increased serum hPAP levels. It is important to determine whether the enzymatic activity of hPAP (or some other structural element) is responsible for this immunosuppression. The applicant proposes to use the 3-D structure of the enzyme to design better inhibitors of hPAP. Once synthesized, the activity of hPAP in the presence of the inhibitors will be determined. The more potent inhibitors will be used to study both NK cell and neutrophil activity in the presence of hPAP as well as inhibited hPAP. The previously reported studies have been flawed in their approach and cannot provide evidence for or against the hypothesis that it is the enzymatic activity of hPAP which results in decreased NK cell and neutrophil activity. The proposed work should enable the determination of whether the above hypothesis is true. If hPAP activity does inhibit host anti-tumor immunological effector mechanisms, including both natural (NK) and acquired (neutrophil) immunity, it can be conceived that this work might lay the foundation for designing a new class of tightly binding hPAP inhibitors which may have a future therapeutic use for either the control of prostate cancer dissemination or for the prevention of sexually transmitted disease infection. A more achievable short-term benefit of the proposed inhibitors might be to use them in the serum hPAP test. Although the serum hPAP test has been replaced with the prostate specific antigen (PSA) test for early detection of prostate cancers, the hPAP test is still widely used to stage the disease and monitor treatment efficacy. Additionally, these inhibitors may prove useful for investigations of the natural substrate of hPAP.